Update on Alcohol, Other Drugs, and Health

Update on Alcohol, Other Drugs, and Health July–August 2013 www.aodhealth.org

Studies on Interventions & Assessments www.aodhealth.org 2

Daily Tenofovir Pre-Exposure Prophylaxis Reduces HIV Transmission among People with Injection Drug Use in Drug Treatment Choopanya K, et al. Lancet. 2013;381(9883):2083–2090. Summary by Alexander Y. Walley, MD, MSc www.aodhealth.org 3

Objectives/Methods Pre-exposure prophylaxis with tenofovir/emtricitabine or tenofovir alone reduces the incidence of HIV infection from sexual transmission by about half, as long as adherence is adequate. Researchers conducted a randomized, placebo-controlled trial of daily pre-exposure prophylaxis with tenofovir among 2413 people in Bangkok, Thailand who injected drugs in the past year. www.aodhealth.org 4

Objectives/Methods (cont’d) • Study sites were 17 drug treatment clinics that offered a package of HIV prevention interventions and directly observed therapy. • Participants chose to receive medication via daily directly observed therapy or monthly visits and could switch monthly. www.aodhealth.org 5

Results At the beginning of the study, 33% of the sample abused methamphetamine, 22% abused heroin, 23% abused midazolam, and 22% were receiving methadone maintenance treatment. At the beginning of the study, the placebo group reported more sexual intercourse in the prior 12 weeks among men who had sex with men (6% versus 4%) and sex with a casual partner (40% versus 36%). Mean follow-up time was 4 years. Mean adherence was 84% of days. Participants received directly observed therapy 87% of the study days. www.aodhealth.org 6

Results (cont’d) • Forty-five percent of participants reported at least one incidence of injection drug use during follow-up. • There were 17 HIV seroconversions (incidence of 0.35 per 100 person-years) in the tenofovir group and 35 (0.68 per 100 person-years) in the placebo group, a 49% reduction in HIV incidence. HIV incidence did not differ until 36 months of follow-up. • Nausea, vomiting (8% versus 5%), and increase in ALT (53% versus 49%) were more common in the tenofovir group. www.aodhealth.org

Comments As in previous trials in sexual risk groups, in this trial among people who inject drugs pre-exposure prophylaxis cut HIV transmission in half. Adherence was key and likely bolstered by the study sites that were drug treatment centers that offered daily observed dosing and methadone maintenance. Analyses did not account for some imbalance at baseline in sexual risk that favored the tenofovir group. www.aodhealth.org 8

Screening and Brief Intervention: USPSTF Update Affirms Recommendations and Highlights Evidence Gaps Moyer VA on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. May 14, 2013 [Epub ahead of print]. doi:10.7326/0003-4819-159-3-201308060-00652. Summary by Richard Saitz, MD, MPH www.aodhealth.org 9

Objectives The U.S. Preventive Services Task Force (USPSTF) has again made recommendations regarding screening and behavioral counseling for unhealthy alcohol use in primary care settings. These new recommendations are essentially unchanged from those of 2004. It recommends that clinicians screen adults and provide persons engaged in risky or hazardous drinking (drinking that results in an increased risk for health consequences) with brief behavioral counseling interventions. It also concludes that the current evidence is insufficient to screen adolescents. www.aodhealth.org 10

Objectives (cont’d) • The recommendation to screen adults is “grade B,” meaning that there is high certainty that the net benefit is moderate. The USPSTF prefers validated single-item screens, the Alcohol Use Disorders Identification Test (AUDIT), and the first 3 items of the AUDIT (AUDIT-C). • A positive screening test should be followed by a brief counseling intervention (at least 6–15 minutes), which is most likely to have efficacy if it is multi-contact. • There is little evidence for efficacy of very brief single interventions. www.aodhealth.org

Comments The evidence and recommendations are clear though very circumscribed: for adults in primary care with hazardous but not harmful or dependent alcohol use, screening and brief—but not too brief—multi-contact counseling can reduce consumption. The USPSTF also highlighted the unknowns: Impact on morbidity, mortality, and quality of life. Efficacy for people with alcohol use disorders (“Limited evidence suggests that brief behavioral counseling interventions are generally ineffective as singular treatments for alcohol abuse or dependence,” an observation that leaves clinicians in a quandary when they identify such persons by screening). Efficacy for adolescents. www.aodhealth.org 12

Comments (cont’d) • Unfortunately, the USPSTF missed an opportunity to correct its prior poor choice to use the term “misuse.” Those with alcohol dependence may take issue with this term. For clinicians, the fact that “misuse” is sometimes used to refer to risky use and at other times used to refer to dependence (i.e., “severe misuse,” according to the U.S. Veterans Health Administration) is confusing at best. • Little is new in this USPSTF statement, but it does again recommend a practice that should be widely disseminated. www.aodhealth.org

Smoking During Medically Managed Opioid Withdrawal is Associated with Increased Craving for Opioids and Nicotine Mannelli P, et al. Nicotine Tob Res. Apr 9, 2013 [Epub ahead of print]. doi: 10.1093/ntr/ntt046. Summary by Alexander Y. Walley, MD, MSc www.aodhealth.org 14

Objectives/Methods Over 80% of people with opioid addiction smoke tobacco. Smoking rates remain high among people who undergo medically managed withdrawal (detoxification). It is not known if smoking cessation during opioid detoxification treatment impacts craving, withdrawal symptoms, or subsequent substance use. Very low doses of naltrexone (0.125 mg–0.25 mg) given concurrently to patients receiving methadone for detoxification has been associated with reduced opioid withdrawal and craving. www.aodhealth.org 15

Objectives/Methods (cont’d) • Using data from a randomized clinical trial of very low-dose naltrexone administered during detoxification, researchers conducted an observational study of craving, opioid treatment completion, and substance use in the next week among 174 subjects categorized as in-treatment smokers, non-smokers, and smokers not allowed to smoke. • Smoking cessation counseling and pharmacotherapy were not offered as part of treatment. www.aodhealth.org 16

Results In-treatment smokers had more severe opioid craving scores—but not more severe opioid withdrawal scores—than non-smokers and smokers not allowed to smoke. In-treatment smokers had higher cigarette craving scores than smokers who were not allowed to smoke. www.aodhealth.org 17

Results (cont’d) • In-treatment smokers were less likely to complete detoxification treatment (59% versus 79%) and smoked more cigarettes in the week after treatment (20 versus 13 per day) than smokers not allowed to smoke. No differences were found in use of opioids, alcohol, cocaine, or cannabis. • Among the in-treatment smokers, those treated with very low-dose naltrexone had lower opioid withdrawal and craving scores than those receiving placebo. www.aodhealth.org 18

Comments This study provides preliminary evidence that smoking cessation during opioid detoxification treatment may improve both opioid and nicotine addiction outcomes by reducing craving. Among those who do smoke during opioid detoxification, very low-dose naltrexone may attenuate the disadvantages of continuing to smoke during treatment. Randomized clinical trials of smoking cessation and very low-dose naltrexone are warranted to determine whether they can improve opioid and nicotine addiction outcomes. www.aodhealth.org 19

Trends in Ambulatory Care for People with Substance Use Disorders Frank JW, et al. Arch Intern Med. 2012;172(22):1759–1760. Summary by Kevin L. Kraemer, MD, MSc www.aodhealth.org 20

Objectives/Methods The extent to which behavioral therapy and pharmacotherapy are used in U.S. ambulatory care to treat people with substance use disorders is not known. Researchers studied data from 2 large, nationally representative, cross-sectional surveys of physicians to identify ambulatory visits from 2001 through 2009 with alcohol and/or drug use disorders (abuse, dependence, intoxication, or withdrawal) as a reason for the visit. www.aodhealth.org 21

Objectives/Methods (cont’d) • Behavioral therapy was defined as provision of mental health counseling, stress management, or psychotherapy at the visit. • Pharmacotherapy was defined as provision of naltrexone, disulfiram, acamprosate, methadone, or buprenorphine at the visit.* The complex survey design allowed for national estimates. * In a personal communication (6/14/2013), Dr. Frank notes: “Methadone recorded in our study likely represents 1) methadone on the patient's medication list but not prescribed by the treating physician, or 2) methadone treatment centers captured within [the survey] sampling frame.” Methadone is not approved for the treatment of opioid dependence through physicians’ offices, only via opioid treatment programs. www.aodhealth.org 22

Results Ambulatory visits for substance use disorders increased from 10.6 million in 2001–2003 to 18 million in 2007–2009; of these, visits for opioid use increased from 772,000 to 4.4 million. Behavioral therapy was provided in about 60% of visits and did not change over time. Pharmacotherapy was provided in 643,000 visits (6% of total) in 2001–2003 and 3.9 million visits (22% of total) in 2007–2009. No treatment for substance use disorders was provided in 36% of visits and did not change significantly over time. 23 www.aodhealth.org

Comments This study indicates a national increase in ambulatory care visits for substance use disorders from 2001 through 2009. It is not clear if this is due to an increase in the underlying population prevalence of substance use disorders, better recognition and coding by providers, or greater care seeking. www.aodhealth.org 24

Comments (cont’d) • The pharmacotherapy data suggest the substantial upward trend for opioid use disorders may be due to increased provision of buprenorphine, which is encouraging. • Although appropriateness of management cannot be discerned from these data, the large number of individuals who received no treatment suggests an opportunity for improving care. www.aodhealth.org 25

Studies on Health Outcomes www.aodhealth.org 26

Roerecke M, et al. Addiction. April 30, 2013 [Epub ahead of print]. doi: 10.1111/add.12231. Summary by Peter D. Friedmann, MD, MPH Alcohol Use Disorders: More Deadly Than Previously Thought www.aodhealth.org 27

Objectives/Methods Alcohol use disorders (AUDs)—comprising alcohol dependence and abuse—affect up to 12% of men and 5% of women in the United States. A seminal review of AUD and all-cause mortality from 1998 indicated a standardized mortality ratio of 1.8 for men and 3.8 for women, but many studies have appeared since then. This meta-analysis of studies up to August, 2012 seeks to update those findings. 28 www.aodhealth.org

Results Eighty-one studies included 221,683 observed deaths among 853,722 people with AUDs. The overall relative risk of death among those with AUDS was 2.98 for men and 4.64 for women. Among treatment samples with diagnosed AUD, relative risk of death was 3.38 for men and 4.57 for women. Among people aged 40 or younger, the relative risk of death increased 9-fold for men and 13-fold for women. 29 www.aodhealth.org

Comments All-cause mortality from alcohol use disorders is higher than previously estimated. The higher risk among treatment samples is probably the result of higher severity of AUDs and more comorbidity, whereas the higher risk among young people is likely the result of lower mortality among the age-specific general population. It remains uncertain whether earlier identification and intervention could reduce these fatalities. www.aodhealth.org 30

Heavy Episodic Drinking in Young, Healthy Adults Increases Risk for Cardiovascular Disease Goslawski M, et al. J Am Coll Cardiol. April 23, 2013 [Epub ahead of print]. doi: 10.1016/j.jacc.2013.03.049. Summary by Jeanette M. Tetrault, MD www.aodhealth.org 31

Objectives/Methods Heavy episodic (binge) drinking is broadly defined as consumption of more than 4 to 5 standard drinks (13 g alcohol/drink) in a two-hour period. Among adults, heavy episodic drinking is associated with an increased risk of cardiovascular events. This increased risk may be explained, in part, by alcohol’s role in endothelial dysfunction. Heavy episodic drinking is common among young, healthy adults with more than half of college students who consume alcoholic beverages reporting it. www.aodhealth.org

Objectives/Methods (cont’d) The purpose of this investigation was to determine whether young adults who participate in heavy episodic drinking have macrovascular and microvascular dysfunction and increased risk of cardiovascular disease compared with their nondrinking counterparts. The authors investigated macrovascular changes via brachial artery endothelial dependent flow mediated vasodilation (FMD) and flow independent nitroglycerin-mediated dilation, and microvascular changes via vasoreactivity of resistance arteries (isolated from gluteal fat biopsies) in 18 to 25-year-old nondrinkers (N=17) and those who participate in heavy episodic drinking (N=19). www.aodhealth.org

Results Subjects with heavy episodic drinking reported 6 +/- 1 heavy episodic drinking episodes per month for an average of 4 +/- 0.6 years. FMD was 8% (+/- 0.7) lower and nitroglycerin-mediated dilations were 20% (+/- 2) lower in people with heavy episodic drinking compared with nondrinkers. Two of three measures of vasoreactivity of resistance arteries were no different between the two groups. www.aodhealth.org 34

Comments This study confirmed that heavy episodic drinking has macrovascular and some microvascular consequences in a sample of young, healthy adults, suggesting an increased risk of cardiovascular events. Given the cross-sectional design and small sample size, these data should be confirmed in future studies. www.aodhealth.org 35

Veliz PT, et al. Am J Pub Health. 2013;103(5):e28–30.Summary by Darius A. Rastegar, MD Participation in Football and Wrestling is Associated with Nonmedical Use of Opioid Medications Among Adolescents www.aodhealth.org 36

Objectives/Methods The prescribing of opioids and the nonmedical use of prescription opioids among adolescents in the United States has grown over the past 15 years. Participation in sports is associated with injuries that may lead to prescribed and nonprescribed opioid use. Data from the annual Monitoring the Future cross-sectional survey of U.S. 8th and 10th grade students in 2010 and 2011 were analyzed for an association between participation in sports and nonmedical use of prescription opioids (NMUPO). www.aodhealth.org 37

Results Overall, 5.5% of 13,636 respondents reported NMUPO in the past 12 months. Those who participated in any competitive sport did not have significantly higher rates of NMUPO (adjusted odds ratio [AOR], 1.17). Participation in football (AOR, 1.50) and wrestling (AOR, 1.49) in particular were associated with a higher rate of NMUPO. Other sports were not associated with higher rates, including ice hockey (AOR, 0.88) and soccer (AOR, 1.04). www.aodhealth.org 38

Results (cont’d) • Hydrocodone (combined with acetaminophen) and oxycodone were the most prevalent prescription opioids used nonmedically. • Other factors associated with NMUPO included nonurban residence, female gender, white race, having ever been suspended from school and being in 10th grade (compared with 8th grade). www.aodhealth.org 39

Comments This study suggests that participation in certain sports is associated with nonmedical prescription opioid use. The authors cite previous research showing that football players and wrestlers have the highest rate of injury among high school athletes to explain why these two sports stood out. While much of this use is probably self-treatment of pain resulting from injuries, it raises the concern that for a minority this will lead to serious problems, including addiction and overdose. www.aodhealth.org 40

Reporting of Methadone-Associated Cardiac Arrhythmias has Increased Kao D, et al. Ann Intern Med. 2013;158:735–740. Summary by Kevin L. Kraemer, MD, MSc www.aodhealth.org 41

Objectives/Methods Opioid-related deaths, which have increased substantially since the 1990s, disproportionately involve methadone. Methadone prolongs the corrected QT interval (QTc) in some patients, which increases the risk of torsade de pointes—a potentially fatal cardiac arrhythmia. www.aodhealth.org

Objectives/Methods (cont’d) Researchers used data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to describe methadone-related cardiac arrhythmia events between 1997 and 2011. They assessed whether reporting increased after the publication of a 2002 report describing an association between methadone and torsade de pointes and whether risk for arrhythmia increased with the concomitant use of methadone and other medications. www.aodhealth.org 43

Results Of 11,015 methadone-related adverse events between 1997 and 2011, 1646 (15%) were for cardiac arrest or ventricular arrhythmia and 379 (3%) were for torsade de pointes or prolonged QTc. Death occurred in 42% of cardiac arrest or ventricular arrhythmia events and 11% of torsade de pointes or prolonged QTc events. www.aodhealth.org 44

Results (cont’d) • Reporting of methadone-associated torsade de pointes and prolonged QTc increased almost twelvefold from before to after the 2002 publication. • The antiretrovirals lamivudine, ritonavir, and zidovudine were the 3 most common concomitant drugs in methadone-associated torsade de pointes and prolonged QTc events. www.aodhealth.org 45 45

Comments These findings highlight the fact that cardiac arrhythmia can be a significant adverse consequence of the provision of methadone. The increase in reporting over time may have been influenced by the 2002 report, but increased methadone prescribing may also be a contributing factor. www.aodhealth.org 46

Comments (cont’d) • The possibility of increased risk among HIV-infected patients receiving antiretrovirals may just reflect a greater likelihood for HIV-infected patients to be prescribed methadone. • Improved physician training on the risks of long-acting opioid therapy is needed. www.aodhealth.org 47 47 47

Relation of Alcohol Intake to the Risk of Dying from Cancer Jin M, et al. Ann Oncol. 2013;24(3):807–816. Summary by R. Curtis Ellison, MD 48 www.aodhealth.org

Objectives/Methods Researchers performed a meta-analysis relating alcohol consumption to all-cancer mortality based on almost 50,000 deaths reported in the literature from 18 prospective cohort studies. 49 www.aodhealth.org

Results In comparison with abstainers or people with occasional alcohol use, the average consumption of ≥50 g of alcohol per day (approximately 4 U.S. standard drinks) was associated with an estimated 32% increased risk of dying from cancer. There was no significant increase in the estimated risk of cancer death for subjects classified as “moderate drinkers” (defined in this study as people who consume 12.6 g to 49.9 g of alcohol per day). 50 www.aodhealth.org

Update on Alcohol, Other Drugs, and Health